A trio of simple optimized axisymmetric kinematic dynamos in a sphere.

Planetary magnetic fields are generated by the motion of conductive fluid in the planet's interior. Complex flows are not required for dynamo action; simple flows have been shown to act as efficient kinematic dynamos, whose physical characteristics are more straightforward to study. Recently, Chen et al. (2018, J. Fluid Mech. 839, 1-32. (doi:10.1017/jfm.2017.924)) found the optimal, unconstrained kinematic dynamo in a sphere, which, despite being of theoretical importance, is of limited practical use. We extend their work by restricting the optimization to three simple two-mode axisymmetric flows based on the kinematic dynamos of Dudley & James (1989, Proc. R. Soc. Lond. A 425, 407-429. (doi:10.1098/rspa.1989.0112)). Using a Lagrangian optimization, we find the smallest critical magnetic Reynolds number for each flow type, measured using an enstrophy-based norm. A Galerkin method is used, in which the spectral coefficients of the fluid flow and magnetic field are updated in order to maximize the final magnetic energy. We consider the t 0 1 s 0 1, t 0 1 s 0 2 and t 0 2 s 0 2 flows and find enstrophy-based critical magnetic Reynolds numbers of 107.7, 142.4 and 125.5 (13.7, 19.6 and 16.4, respectively, with the energy-based definition). These are up to four times smaller than the original flows. These simple and efficient flows may be used as benchmarks in future studies.

Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage.

OBJECTIVES: To investigate the multi-biomarker disease activity (MBDA) score by comparison with imaging findings in an investigator-initiated rheumatoid arthritis (RA) trial (HURRAH trial, NCT00696059). METHOD: Fifty-two patients with established RA initiated adalimumab treatment and had magnetic resonance imaging (MRI), ultrasonography (US), computed tomography (CT), and radiography performed at weeks 0, 26, and 52. Serum samples were analysed using MBDA score assays and associations between clinical measures, MBDA score, and imaging findings were investigated. RESULTS: The MBDA score correlated significantly with MRI synovitis (rho = 0.65, p < 0.001), MRI bone marrow oedema (rho = 0.36, p = 0.044), and US power Doppler (PD) score at week 26 (rho = 0.35, p = 0.039) but not at week 0 or week 52. In the 15 patients who had achieved a Disease Activity Score based on C-reactive protein (DAS28-CRP) < 2.6 at week 26, MRI and/or US detected subclinical inflammation and 13 (87%) had a moderate/high MBDA score. For the cohort with available data, none of the four patients in MBDA remission (score ≤ 25) at week 26 had progression of imaging damage from baseline to week 52 whereas progression was observed in three out of nine (33%) and seven out of 21 (33%) patients with moderate (30-44) and high (> 44) MBDA scores, respectively. CONCLUSIONS: In this cohort, the MBDA score correlated poorly with MRI/US inflammation. However, the MBDA score and MRI/US were generally concordant in showing signs of inflammation in most patients in clinical remission during anti-tumour necrosis factor (anti-TNF) therapy. MBDA scores were elevated in all patients with structural damage progression.

Relation between HIV-1 and hepatitis C viral load in patients with hemophilia.

Coinfection with hepatitis C virus (HCV) and HIV-1 is common in patients with hemophilia and in intravenous drug users. Little, however, is known about the relation between HIV-1 and HCV coinfection and the effects on HCV clearance and pathogenesis. We examined data from 207 HIV-1-infected and 126 HIV-1-uninfected patients with hemophilia enrolled in the multicenter Hemophilia Growth and Development Study. Participants were observed during prospective follow-up for approximately 7 years with annual measurements of alanine aminotransferase (ALT), CD4+ cells, and HCV and HIV-1 RNA levels. Clearance of HCV was more likely to occur in those uninfected with HIV-1 (14.3 versus 2.5%; odds ratio [OR] 4.79; 95% confidence interval [CI], 1.63-14.08, p =.005) and was more common with decreasing age (OR, 1.23; 95% CI, 1.04-1.47; p =.017). HCV RNA levels were higher throughout the 7 years of follow-up in those HIV-1-infected (p <.001). In the HIV-1-infected participants, baseline CD4+ cells were inversely related to HCV RNA with every 100-cell increase associated with a 0.19 log10 copy/ml decrease in HCV RNA (p =.002), and HIV-1 and HCV RNA levels were directly related (p =.008). Increasing HCV RNA levels were also associated with significantly higher ALT levels regardless of HIV-1 infection status. These results demonstrate that HIV-1/HCV co-infection is associated with a reduced likelihood of HCV clearance and that higher levels of HCV RNA are associated with increased hepatic inflammation.

The effect of plasma human immunodeficiency virus RNA and CD4(+) T lymphocytes on growth measurements of hemophilic boys and adolescents.

OBJECTIVE: The investigation examined the associations of plasma human immunodeficiency virus (HIV) RNA and CD4(+) T lymphocytes with height, weight, skeletal maturation, testosterone levels, and height velocity for hemophilic children and adolescents with HIV infection in the Hemophilia Growth and Development Study. STUDY DESIGN: Two hundred seven participants were evaluated over 7 years. RESULTS: A threefold increment in baseline plasma HIV RNA was associated with a 0.98-cm decrease in height and a 1.67-kg decrease in weight; 100-cells/microL decrements in baseline CD4(+) were associated with a 2.51-cm decrease in height and a 3.83-kg decrease in weight. Participants with high plasma HIV RNA (>3125 copies/mL) experienced significant delay in achieving maximum height velocity and lower maximum velocity compared with those with low viral load. The high CD4(+) (>243)/low plasma HIV RNA group had earlier age at maximum height velocity compared with the other 3 groups and higher maximum height velocity compared with the low CD4(+)/high plasma HIV RNA and low CD4(+)/low plasma HIV RNA groups. Decrements in CD4(+) were associated with decreases in bone age and testosterone level. CONCLUSIONS: CD4(+) and HIV RNA were important in predicting growth outcomes.

Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs.

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.

In vivo emergence of drug-resistant mutations at less than 50 HIV-1 RNA copies/mL that are maintained at viral rebound in longitudinal plasma samples from human immunodeficiency virus type-1-infected patients on highly active antiretroviral therapy.

OBJECTIVE: Emergence of human immunodeficiency virus type-1 (HIV-1) genotypic drug resistance is generally attributed to noncompliance, poorly absorbed drugs, or drug-to-drug interaction. Attempts to determine emerging genotypic drug resistance from study subjects on highly active antiretroviral therapy (HAART) relied on insensitive polymerase chain reaction (PCR) techniques, revealing wild type HIV-1 or precursor resistant genotypes from few plasma samples successfully amplified with <50 copies/mL. STUDY DESIGN/METHODS: In this analysis, using Applied Biosystems' ViroSeq HIV-1 Genotyping Systems, Version 2.0 (Applied Biosystems, Foster City, CA, USA) and the supplemental, for research use only, nested PCR primers, genotypic drug resistance was determined in longitudinal plasma samples from 11 study subjects on HAART. RESULTS: In 4 of 11 study subjects, newly emerging genotypic primary resistant mutations were detected in plasma samples with <50 copies/mL. Most of these primary drug-resistant mutations were detected in subsequent longitudinal samples with detectable viral load (viral breakthrough). CONCLUSIONS: This analysis suggests sufficient viral replication <50 copies/mL to generate genotypic drug resistance in study subjects on suppressive HAART.

Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214.

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection.

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

Effects of plasma HIV RNA, CD4+ T lymphocytes, and the chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. Hemophilia Growth and Development Study.

We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number.

Influenza vaccination of human immunodeficiency virus (HIV)-infected adults: impact on plasma levels of HIV type 1 RNA and determinants of antibody response.

We assessed the effect of influenza vaccination on plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and the impact of age, plasma HIV-1 RNA level, CD4 cell count, and anti-HIV therapy on immune response. Forty-nine adults (mean age, 38.7 years; mean CD4 cell count +/- SD, 190 +/- 169/mL; mean plasma HIV-1 RNA level +/- SD, 154,616 +/- 317,192 copies/mL) were immunized. Elevations of > or = 0.48 log in plasma HIV-1 RNA levels occurred in two (4%) of 49 subjects within 4 weeks of vaccination. A fourfold or greater increase in antibody titer occurred in 13 (45%) of 29 subjects, correlating directly with CD4 cell count (P = .002) and inversely with plasma HIV-1 RNA level (P = .034). By multivariate analysis, CD4 cell count was a stronger predictor of antibody response than was plasma HIV-1 RNA level. We conclude that increases in plasma HIV-1 RNA levels following influenza vaccination are rare and transient and that antibody response is impaired with CD4 cell counts of < 100/mL and plasma HIV-1 RNA levels of > 100,000 copies/mL. Prospective trials are needed to evaluate the impact of highly active therapy on immune response after vaccination.

Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women.

The transmission of perinatal hepatitis C virus (HCV) infection was studied retrospectively in 62 infants born to 54 HCV- and human immunodeficiency virus (HIV)-coinfected women enrolled in a prospective natural history study of HIV transmission. Infant HCV infection was assessed by nested RNA polymerase chain reaction. The overall rate of vertical HCV transmission was 16.4% (9/62). Most HCV-infected children did not develop antibodies to HCV. The rate of HCV infection was higher among HIV-infected infants (40%) than among HIV-uninfected infants (7.5%; odds ratio, 8.2; P = .009). This difference in transmission was not related to differences in maternal HCV load, as measured by branched DNA assay, or mode of delivery. Why HIV-infected infants of HCV- and HIV-coinfected women have significantly higher rates of perinatal HCV transmission remains to be elucidated. The rate of HCV transmission in HIV-uninfected infants of HCV- and HIV-coinfected women is similar to that reported for infants born to HIV-seronegative mothers.

Quantification of human immunodeficiency virus type 1 RNA levels in plasma by using small-volume-format branched-DNA assays.

We have developed small-volume (50 or 250 microl)-format branched-DNA assays for human immunodeficiency virus type 1 (HIV-1) RNA for use with specimens in which the volume is limited and/or a high viral load is anticipated. These formats exhibited good correlation with the standard 1-ml format; high specificity, reproducibility, and linearity; and no significant difference in the quantification of HIV-1 subtypes.

Coronary artery stenoses: assessment with contrast-enhanced electron-beam CT and axial reconstructions.

PURPOSE: To evaluate the usefulness of electron-beam computed tomography (CT) for identification of coronary artery stenoses. MATERIALS AND METHODS: Coronary angiography and contrast material-enhanced, electrocardiographically triggered electron-beam CT of the heart were performed in 23 patients. With axial CT images and axial maximum intensity projection reconstructions, the coronary arteries were assessed by two observers blinded to the results of angiography. RESULTS: Cardiac motion artifact (unsharpness) precluded evaluation of the right coronary artery (RCA) in six subjects and the left circumflex coronary artery (LCX) in one patient. With the vessels degraded by motion artifact eliminated from analysis, overall sensitivity of electron-beam CT for hemodynamically significant stenoses was 88%, and specificity was 79%. In the left anterior descending coronary artery (LAD), sensitivity was 93% and specificity was 63%; in the LCX, sensitivity was 100% and specificity was 67%; and in the RCA, sensitivity was 67% and specificity was 77%. The presence of coronary artery calcification did not have an effect on sensitivity for stenoses, but it did decrease specificity. CONCLUSION: Electron-beam CT angiography can depict hemodynamically significant stenoses in the LAD and LCX with a sensitivity of more than 90%. The presence of coronary artery calcification resulted in decreased specificity but no appreciable change in sensitivity.

Proinflammatory cytokine and human immunodeficiency virus RNA levels during early Mycobacterium avium complex bacteremia in advanced AIDS.

The relationship between Mycobacterium avium complex (MAC) bacteremia and proinflammatory cytokine and human immunodeficiency virus type 1 (HIV-1) RNA levels in AIDS was investigated. During a prospective study, blood samples were drawn monthly for mycobacterial cultures. Sera were available at baseline and onset of MAC bacteremia from 20 cases and at corresponding times from 19 controls. Mean interleukin-6 (IL-6) levels were 154% greater at the time of MAC bacteremia in cases than in controls. The IL-6 levels correlated with body temperature, serum tumor necrosis factor (TNF-alpha) levels, and alkaline phosphatase levels (P < or = .004 for each). Although TNF-alpha levels tended to rise more in MAC patients than in controls, the difference was not significant. However, among both cases and controls, serum TNF-alpha levels rose significantly from baseline to the time of last sample, irrespective of MAC infection (P = .015). Bacteremia was not associated with increased serum HIV-1 RNA levels. Thus, early MAC bacteremia is associated with increases in serum IL-6 levels, while TNF-alpha levels rise over time during advanced AIDS.

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients.

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.

Correlation of virus load in plasma and lymph node tissue in human immunodeficiency virus infection. INCAS Study Group. Italy, Netherlands, Canada, Australia, and (United) States.

The impact of long-term changes in plasma viremia, produced by effective combination antiretroviral therapy, on human immunodeficiency virus (HIV) burden within tissue reservoirs is unknown. Fifteen patients who had received at least 1 year of therapy with two or three drug combinations of zidovudine, didanosine, and nevirapine had suitable samples of lymph node tissue obtained by ultrasound-guided core needle biopsy. HIV RNA was extracted from homogenized tissue samples and quantitated using a modified branched DNA assay. Results were correlated with antiretroviral treatment effect on the basis of plasma virus load measurements over the preceding 12-18 months. A statistically significant negative correlation was observed between magnitude of treatment effect on plasma viremia and lymph node virus load. These data suggest that combinations of antiretroviral drugs that produce sustained suppression of plasma HIV RNA may also be able to reduce the virus burden in lymphoid tissues.

Quantification of cytomegalovirus DNA in peripheral blood leukocytes by a branched-DNA signal amplification assay.

Quantification of cytomegalovirus (CMV) DNA in blood may aid in the identification of patients at highest risk for developing CMV disease, the evaluation of new therapeutics, and the prompt recognition of drug-resistant CMV strains. A branched-DNA (bDNA) assay was developed for the reliable quantification of CMV DNA in peripheral blood leukocytes. The bDNA assay allowed for the highly specific and reproducible quantification of CMV DNA in clinical specimens. Furthermore, the bDNA assay was at least as sensitive as culture techniques and displayed a nearly 3 log10 dynamic range in quantification. Changes in CMV DNA levels measured by the bDNA assay in a human immunodeficiency virus-positive patient undergoing therapy were consistent with CMV culture, antigen, and genotype results and correlated with disease progression and resistance markers. The bDNA assay for the quantification of CMV DNA may provide a useful tool that can be used to aid physicians in monitoring disease progression, evaluating therapeutic regimens, and recognizing viral resistance and drug failure.

Variance of plasma human immunodeficiency virus type 1 RNA levels measured by branched DNA within and between days.

Previous studies have shown that CD4-positive T cells vary in a predictable manner over 24 h. This diurnal variance has significant clinical implications. Recently, viral RNA measurements have been increasingly used as a standard marker in the management of human immunodeficiency virus (HIV)-infected patients. Little detailed analysis of the variability of this marker has been conducted. To define the variance of plasma HIV-1 RNA levels within days, 11 clinically stable patients with established HIV infection and a baseline viral RNA level >40,000 copies/mL were studied. Following the patients' admission to an inpatient research unit, plasma samples were obtained frequently over 48 h and analyzed for HIV-1 RNA levels by use of a quantitative branched chain DNA assay (bDNA). No diurnal pattern was detected. In these clinically stable patients, viral RNA levels exhibited a variance of approximately 0.4 log.